An AKR/J murine carcinoma-like tumor was generated in tissue culture from an undifferentiated fibrosarcoma. An autologous immune response was generated against the carcinoma in vivo and in vitro. Subcutaneous injection of low numbers of the carcinoma cells resulted in a period of tumor growth followed by tumor regression. Lymphocytes from regressing mice were specifically cytotoxic for carcinoma target cells. Cytotoxic effector cells could also be generated in vitro against the carcinoma, and the injection of cells containing effectors protected host mice from a lethal inoculum of the tumor. T-cell-mediated and antibody-mediated cytotoxic studies were performed to determine if new antigens were expressed on the carcinoma cell line. The results from both types of experiments suggested that a loss of a private H-2Dk specificity had occurred with a concomitant gain of a private H-2Dd specificity. Rejection of the tumor in vivo and the generation of cytotoxic effector cells in vitro was shown to be associated with this loss and gain of major histocompatibility complex (MHC) controlled antigens.